Background: Several concerns have emerged on the higher risk of in-stent thrombosis after drug-eluting stent (DES) implantation, especially in the setting of STEMI patients. Few data have even been reported in high-risk patients, such as those with anterior MI. Therefore this represents the aim of the current study. Methods: The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL). We examined all completed randomized trials of DES for STEMI. The following key words were used for study selection: randomized trial, myocardial infarction, reperfusion, primary angioplasty, stenting, DES, sirolimus-eluting stent (SES), Cypher, paclitaxel-eluting stent (PES), Taxus. No language restrictions were enforced. Results: Individual patient's data were obtained from 11 out of 13 trials, including a total of 2,782 patients with anterior MI [1,739 or 62.5 % randomized to DES and 1,043 or 37.5 % randomized to bare-metal stent (BMS)]. At long-term follow-up, no significant benefit was observed with DES as compared to BMS in terms of mortality [9.8 vs 10.9 %, HR (95 % CI) = 0.81 (0.61, 1.07), p = 0.13, p heterogeneity = 0.18], reinfarction [8.8 vs 6.4 %, respectively; HR (95 % CI) = 1.14 (0.80, 1.61), p = 0.47, p heterogeneity = 0.82], and stent thrombosis [5.6 vs 5 %, OR (95 % CI) = 0.88 (0.59, 1.30), p = 0.51, p heterogeneity = 0.65], whereas DES was associated with a significant reduction in terms of target-vessel revascularization (TVR) [13.7 vs 23.4 %; OR (95 % CI) = 0.56 (0.46, 0.69), p < 0.0001, p het = 0.81] that was observed at both early (within 1 year) [7 vs 14.7 %, HR (95 % CI) = 0.56 (0.46, 0.69), p < 0.0001, p het = 0.81] and late (>1 year) follow-up [7.2 vs 9 %, HR (95 % CI) = 0.67 (0.47, 0.96), p = 0.03, p het = 0.96]. Conclusions: This study showed that among patients with anterior STEMI undergoing primary angioplasty, SES and PES, as compared to BMS, are associated with a significant reduction in TVR at long-term follow-up. No concerns were found with the use of first-generation DES in terms of mortality.